OBJECTIVE - Population data suggest that alcohol consumption may influence the risk of diabetes in a biphasic manner, but this has not been tested by any controlled interventions. The object of this study was to determine whether reducing alcohol intake in moderate-to-heavy drinkers (40-110 g/day) results in improvement in insulin sensitivity.RESEARCH DESIGN AND METHODS - A 4-week run-in period where subjects maintained their usual drinking pattern was followed by randomization to a two-way cross-over intervention study. In each of two 4-week treatment interventions, subjects either substituted their usual alcohol intake with a 0.9% alcohol beer or maintained their usual alcohol intake. At the end of each 4-week period, insulin sensitivity as determined by the low-dose insulin glucose infusion test and the homeostasis model assessment (HOMA) score, and biomarkers of alcohol consumption (gamma-glutamyl transpepticlase [gamma-GT] and HDL cholesterol) were measured.RESULTS - A total of 16 healthy men aged 51.0 +/- 2.7 (mean SEM) years with a BMI of 26.4 +/- 0.61 kg/m(2) completed the study. There was a large reduction in alcohol intake (72.4 +/- 5.0 vs. 7.9 +/- 1.6 g/day, P < 0.001) and significant reductions in γ-GT (geometric mean 24.4 units/l [95% CI 19.7-30.2] vs. 18.6 units/l [15.5-22.2], P < 0.01) and HDL cholesterol (1.36 +/- 0.07 vs. 1.13 +/- 0.07 mmol/l, P < 0.001). There was no effect of alcohol on insulin sensitivity index (ISI), fasting insulin, glucose, or HOMA score.CONCLUSIONS - A substantial reduction in alcohol intake from 7.2 to 0.8 standard drinks per day in healthy men did not change insulin sensitivity as measured by ISI or HOMA score.